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PMID: 16914522 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The mitochondrial fission protein hFis1 requires the endoplasmic reticulum gateway to induce apoptosis.

Molecular biology of the cell ·Vol. 17 ·No. 11 ·2006-11-00 ·Pages 4593-605

Alirol E, James D, Huber D, Marchetto A, Vergani L, Martinou JC, Scorrano L

Abstract

Mitochondrial fission ensures organelle inheritance during cell division and participates in apoptosis. The fission protein hFis1 triggers caspase-dependent cell death, by causing the release of cytochrome c from mitochondria. Here we show that mitochondrial fission induced by hFis1 is genetically distinct from apoptosis. In cells lacking the multidomain proapoptotic Bcl-2 family members Bax and Bak (DKO), hFis1 caused mitochondrial fragmentation but not organelle dysfunction and apoptosis. Similarly, a mutant in the intermembrane region of hFis1-induced fission but not cell death, further dissociating mitochondrial fragmentation from apoptosis induction. Selective correction of the endoplasmic reticulum (ER) defect of DKO cells restored killing by hFis1, indicating that death by hFis1 relies on the ER gateway of apoptosis. Consistently, hFis1 did not directly activate BAX and BAK, but induced Ca(2+)-dependent mitochondrial dysfunction. Thus, hFis1 is a bifunctional protein that independently regulates mitochondrial fragmentation and ER-mediated apoptosis.

MeSH Terms
Adenosine Triphosphatases/metabolism Animals Apoptosis/physiology Cell Respiration/physiology DNA Mutational Analysis Endoplasmic Reticulum/metabolism Fibroblasts/cytology,ultrastructure Humans Membrane Proteins Mice Mitochondria/metabolism,ultrastructure Mitochondrial Membranes/metabolism Mitochondrial Proteins/chemistry,genetics,metabolism Permeability Protein Structure, Tertiary Reactive Oxygen Species/metabolism bcl-2 Homologous Antagonist-Killer Protein/deficiency bcl-2-Associated X Protein/deficiency
Chemicals
FIS1 protein, human Membrane Proteins Mitochondrial Proteins Reactive Oxygen Species bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein Adenosine Triphosphatases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Alirol Emilie
Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, I-35129 Padova, Italy.
James Dominic
Huber Denise
Marchetto Andrea
Vergani Lodovica
Martinou Jean-Claude
Scorrano Luca
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.e06-05-0377
Published
2006-11-00
Epub
2006-00-16
Pages
4593-605
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC1635393
Subset
IM
Grants
Telethon · TCP02016 · Italy
External Links
PubMed source DOI: 10.1091/mbc.e06-05-0377 PMC Full Text View journal details
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